Although significant advances have been made in the past 30 years in the understanding of HIV pathogenesis, there is still a need for development of effective antiretroviral therapy for the long-term management of HIV infection in infants, children and adults, as well as antiretroviral interventions to prevent HIV in women, who have the greatest burden of HIV in sub-Saharan Africa, children, in discordant couples, men who have sex with men and certain high risk heterosexual populations. With 1.9 million people receiving antiretroviral therapy in South Africa alone, further clinical problems related to durability of therapy, viral resistance and adverse events are emerging. Moreover, male circumcision, access to voluntary counseling and HIV testing, male and female condoms and other behavioral interventions are important components of governments' strategies to control HIV, new HIV Infections remain persistently high. Biomedical interventions are urgently required especially to protect women. Without an effective HIV vaccine, it is doubtful whether eradication of the HIV infection is feasible. TB/HIV co-infection adds significant morbidity and mortality to HIV infected infants, children and adults, and is the leading cause of death in South Africa. More potent, shorter and less toxic treatment for TB, to prevent TB, and to treat drug resistant TB are desperately needed. Our proposed KAREBELO CTU, comprises a group of internationally renowned scientists, the majority of whom are based in South Africa, are women, and come from diverse racial and ethnic backgrounds. Our eight Clinical Research Sites forming the KARABELO Clinical Trials Unit (CTU) are strategically positioned in areas of high HIV prevalence and Incidence and include informal settlements, maternity units, TB clinics and an MDR hospital, cities and migrant laborers to answer critical questions in the control and prevention of both HIV and TB. The CRSs, seven of which are in South Africa and one in Long Island, New York have capacity to address critical clinical research agendas of four selected NIAID Clinical Research networks: vaccines to prevent HIV infection; microbicides to prevent HIV infection; HIV/AIDS and HIV-associated infections in infants and maternal populations; and therapeutics for HIV/AIDS and HIV-associated infections and pathogens in adults. RELEVANCE: HIV and TB continue to be one of greatest threats to human health. Progress in understanding and managing HIV, although revolutionary, and translated into practice at an advanced rate, has not yet yielded an effective HIV vaccine, microbicide or cure. Similarly, despite advancements in TB management, an effective vaccine for TB remains elusive.